CN1155570C - Novel cyano-indole serotonin reextracted inhibitor compound, its preparation process and medicinal compositions having same - Google Patents
Novel cyano-indole serotonin reextracted inhibitor compound, its preparation process and medicinal compositions having same Download PDFInfo
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Abstract
Compound of formula (I):wherein:R1 and R2 each independently of the other represents hydrogen or alkyl, A represents alkylene, alkenylene or alkynylene,G1 representswherein R3 and R4 each independently of the other represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl or optionally substituted arylalkyl, or G1 represents heterocycloalkyl optionally substituted by alkyl, cycloalkyl, cycloalkylalkyl, nitrile, carboxy, alkoxycarbonyl, carbamoyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
Description
Technical field
The present invention relates to new cyano group-indole serotonin reuptaking inhibitor compound, its preparation method and contain their pharmaceutical composition.
Background of invention
Described with indole ring and 2,3-dihydro-1, the compound that 4-benzodioxin (benzodioxine) ring is combined as feature has serotonin reuptake transporter rejection characteristic (WO9717343).Also claimed in application EP814084 have effect at the nuclear substituted indoles of virtue in the serotonin reuptake transporter site.Other compound with correlation properties is claimed and have a benzopyran structure in application WO9633710.
Serotonin reuptake inhibitor constitutes one group of diversified therapeutical agent.They are used to treat with axoneuron cynapse place serotonin and lack relevant disease.To suppress serotonin reuptake transporter be a kind of method of recovering neurotransmission by combining with translocator or presynaptic receptor.
Application of compound with those rejection characteristics can replace tricyclic antidepressants or oxidase inhibitor at treatment depression and relative disease (Annals of Pharmacotherapy, 1994,28,1359), panic attack and obsessive-compulsive disorder (HumanPsychopharmacology, 1995,10,5199) application in.Usefulness (psychopharmacology magazine (Journal ofPsychopharmaco-logy) with compound of this pharmacological property, 1994,8,238) because of they better tolerance (international clinical psychopharmacologies (International Clinical Psychopharmacology), 1995,9 supplementary issues 4,33) and use the fact of safer (pharmacology annual report (Annals of Pharmacology), cited literature 2) and strengthened.
Summary of the invention
The compounds of this invention is characterised in that indole ring, and it is replaced by cyano group and replaced by the aminoalkyl group chain on indole nitrogen in the aromatic ring part.This new structure has to 5-HT them in addition
2CThe high affinity of acceptor, intensive serotonin reuptake transporter rejection characteristic.So they will can be used in treatment dysthymia disorders, panic attack, obsessive-compulsive disorder, phobia, impulsion disease, bulimia nervosa and the anxiety disorder relevant with drug abuse.
Detailed Description Of The Invention
The present invention relates to formula (I) compound, its enantiomorph, diastereomer and with the additive salt of pharmaceutically acceptable acid or alkali:
Wherein:
R
1And R
2Represent hydrogen atom or straight or branched (C independently of one another
1-C
6) alkyl,
A represents straight or branched (C
1-C
6) alkylidene group, straight or branched (C
2-C
6) alkylene group or straight or branched (C
2-C
6) alkynylene,
G
1The expression group
R wherein
3And R
4Represent hydrogen atom, straight or branched (C independently of one another
1-C
6) alkyl, (C
3-C
8) cycloalkyl, wherein moieties is straight or branched (C
3-C
8) cycloalkyl-(C
1-C
6) alkyl, the optional aryl that replaces, wherein moieties is the aryl-(C of the optional replacement of straight or branched
1-C
6) alkyl, the optional heteroaryl that replaces or wherein moieties be the heteroaryl-(C of the optional replacement of straight or branched
1-C
6) alkyl,
Perhaps G
1The expression Heterocyclylalkyl is chosen wantonly by any one articulating point bonding and on any one site of ring with A and to be replaced by following groups: straight or branched (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, wherein moieties is straight or branched (C
3-C
8) cycloalkyl-(C
1-C
6) alkyl, itrile group, carboxyl, straight or branched (C
1-C
6) alkoxyl group-carbonyl, formamyl (optionally replace by one or two substituting group: straight or branched (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, the optional phenyl that replaces and/or the optional benzyl that replaces), the optional aryl that replaces, wherein moieties is the aryl-(C of the optional replacement of straight or branched
1-C
6) alkyl, the optional heteroaryl that replaces or wherein moieties be the heteroaryl-(C of the optional replacement of straight or branched
1-C
6) alkyl.
" Heterocyclylalkyl " is understood that to mean saturated 4-8 unit cyclic group, contains 1 or 2 nitrogen and/or Sauerstoffatom, is selected from piperazinyl, 1, the group of 4-diaza (diazepan) base and pyrrolidyl.
" aryl " is understood that to refer to be selected from the group of phenyl and naphthyl.
" heteroaryl " is understood that to refer to monocycle or two rings, unsaturated or part is undersaturated, is selected from pyridyl, pyrimidyl, indolinyl, thiazole and pyrimidyl and dihydroquinazoline base.
" the optional replacement " the described group of expression that is used for term " aryl ", " aralkyl " " heteroaryl " and " heteroarylalkyl " is replaced by a following groups on its circular part: halogen atom and/or straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, wherein moieties is the perhalogeno (C of straight or branched
1-C
6) alkyl group, should understand heteroaryl and heteroarylalkyl and also can be replaced by oxo group.
In the pharmaceutically acceptable acid, can mention hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphonic acids, acetate, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, methylsulfonic acid, dextrocamphoric acid etc. in the indefiniteness mode.
In the pharmaceutically acceptable alkali, can mention sodium hydroxide, potassium hydroxide, triethylamine, TERTIARY BUTYL AMINE etc. in the indefiniteness mode.
Advantageously, the present invention relates to wherein 5-position bonded formula (I) compound of cyano group and indyl.
Another favourable aspect of the present invention relates to wherein 6-position bonded formula (I) compound of cyano group and indyl.
Preferred Heterocyclylalkyl is a piperazine, 1,4-diaza , tetramethyleneimine (3-pyrrolidyl) and piperidines group.It is favourable that those groups are selected from that following group replaces: the optional aryl (for example, phenyl) that replaces, wherein moieties is the aryl-(C of the optional replacement of straight or branched
1-C
6) alkyl (for example, benzyl, styroyl or phenyl propyl) and the optional heteroaryl that replaces are (for example, piperazine, pyridine, 2-oxo-2,3-dihydro-1H-indoles, 5-oxo-5H-[1,3] thiazole also [3,2-a] pyrimidine or 2,4-dioxo-1,4-dihydro-3-(2H)-quinazoline).
In preferred compound of the present invention, especially can mention:
1-{3-[4-(5-methoxyl group-4-pyrimidyl)-1-piperazinyl] propyl group }-the 1H-indole-6-carbonitrile,
1-{[1-(2-chlorobenzene ethyl)-3-pyrrolidyl] methyl }-the 1H-indole-6-carbonitrile,
The present invention also relates to the method for preparation formula (I) compound, it is characterized in that formula (II) compound is used as raw material:
R wherein
1And R
2Each defines suc as formula (I),
After formula (II) compound is handled in alkaline medium, it can be stood
The effect of → formula (III) compound:
P-A-G
1 (III)
Wherein A and G
1Define suc as formula (I), and P represents leavings group (for example tosyl group),
Obtain formula (I) compound,
Perhaps
The effect of → formula (IV) compound:
Hal-A-OH (IV)
Wherein A defines suc as formula (I), and Hal represents halogen atom, obtains the formula V compound:
R wherein
1, R
2Define suc as formula (I) with A,
After being converted into leavings group, the formula V compound is stood the effect of formula (VI) compound in alkaline medium with hydroxyl functional group bromination or with the latter:
G
1-H (VI)
G wherein
1Define suc as formula (I),
Obtain formula (I) compound, should understand and work as group G
1When representing unsubstituted Heterocyclylalkyl, can use conventional organic chemical reactions that it is in the end replaced in the step so that the defined substituting group of drawing-in system (I),
Formula (I) compound:
-if desired, can be according to conventional purification technique purifying,
If-suitable, can be separated into its isomer according to conventional isolation technique,
-if desired, be converted into its additive salt with pharmaceutically acceptable acid or alkali.
The present invention also relates to pharmaceutical composition, its comprise separately at least a formula (I) compound as activeconstituents or with one or more inertia, nontoxic pharmaceutically acceptable vehicle or carrier combinations.
In pharmaceutical composition of the present invention, especially can mention those composition, tablet or dragees that are applicable to oral, non-enteron aisle or nose administration, sublingual tablet, gelatine capsule, lozenge, suppository, creme, ointment, skin with gel etc.
Useful dosage changes according to the character of age of patient and body weight, disease and severity and route of administration, and described route of administration can be oral, intranasal, rectum or parenterai administration.For the treatment of 1-3 administration in per 24 hours, unitary dose is generally 0.1-500mg.
The following example is used for explanation but limits the present invention never in any form.
Employed raw material is known product or can prepares according to currently known methods.
Embodiment 1:1-{3-[4-(5-methoxyl group-4-pyrimidyl)-1-piperazinyl] propyl group }-1H-indole-6-carbonitrile dihydrochloride
Step a:1-(3-hydroxypropyl)-1H-indole-6-carbonitrile
Under 20 ℃, 0.776mol (87g) potassium tert.-butoxide is added in the solution of 0.703mol (100g) 6-cyanoindole in the 2500ml tetrahydrofuran (THF).Stir after 15 minutes, add 1.41mol (196g) 3-bromo-1-propyl alcohol and also at room temperature reaction mixture was stirred 24 hours.After concentrating, resistates is dissolved in the 1000ml methylene dichloride, and washs organic phase successively with the 500ml saturated nacl aqueous solution then with 500ml water, and dry then organic phase is also concentrated, obtains expecting product.
Step b:1-(3-bromopropyl)-1H-6-nitrile
Under 20 ℃, the solution of 0.78mol (204g) triphenylphosphine in the 600ml acetonitrile is added in rapid described compound of 0.7mol (140g) previous step and the solution of 0.85mol (280g) tetrabromomethane in the 2000ml acetonitrile.Stir after 4 hours,, use cyclohexane/ethyl acetate mixture 90/10, obtain expecting product as eluent by coming the purification reaction mixture at the enterprising circumstances in which people get things ready for a trip of silica gel spectrum chromatography.
Step c:1-{3-[4-(5-methoxyl group-4-pyrimidyl)-1-piperazinyl] propyl group }-1H-indole-6-carbonitrile dihydrochloride
The rapid described compound of 11.4mmol (3g) previous step, 12.5mmol (2.43g) 5-methoxyl group-4-(1-piperazinyl) pyrimidine and the 1.3g yellow soda ash mixture heating up in the 60ml acetonitrile was refluxed 3 hours.Cooling and concentrate after, resistates is dissolved in the 100ml methylene dichloride, organic phase washes with water, dry and concentrate.The gained resistates uses methylene chloride/ammonia mixture 90/10/1 as eluent at the enterprising circumstances in which people get things ready for a trip spectrum of silica gel chromatography purification.By obtaining corresponding dihydrochloride with the effect of volumetric soiutions of HCl in ethanol.
Fusing point: 178-180 ℃
Elemental microanalysis:
C H N Cl
% calculated value 56.12 5.84 18.71 15.78
% measured value 56.85 6.04 18.70 14.98
Embodiment 2:1-[3-(dimethylamino) propyl group]-1H-indole-6-carbonitrile hydrochloride
Mixture in the 60ml acetonitrile heated 1 hour down at 70 ℃ with 11.4mmol (3g) embodiment described compound of 1 step b and 22.8mmol (2.6g) 40% dimethylamine agueous solution.After the cooling, concentrated reaction mixture, and the gained resistates is dissolved in the 100ml methylene dichloride.Organic phase washes with water, dry and concentrate, obtain expecting product.By obtaining corresponding hydrochloride with the effect of volumetric soiutions of HCl in ethanol.
Fusing point: 168-170 ℃
Elemental microanalysis:
C H N Cl
% calculated value 63.75 6.88 15.93 13.44
% measured value 62.90 6.88 15.50 12.39
Embodiment 3:1-{3-[benzyl (methyl) amino] propyl group }-the 1H-indole-6-carbonitrile
Obtain expecting product according to the described method of embodiment 1 step c, just replace 5-methoxyl group-4-(1-piperazinyl) pyrimidine with N-methyl-benzyl amine.
Fusing point: 68-70 ℃
Elemental microanalysis:
C H N Cl
% calculated value 70.68 6.52 12.36 10.43
% measured value 70.43 6.54 12.17 10.55
Embodiment 4:1-(3-pyrrolidyl methyl)-1H-indole-6-carbonitrile hydrochloride
Step a:3-[(6-cyano group-IH-indoles-1-yl) methyl]-1-pyrrolidine carboxylic acid tertiary butyl ester
The 77mmol potassium tert.-butoxide is added in the solution of 70mmol 6-cyanoindole in 400ml hydrogen furans.After the stirring at room 10 minutes, be added in the 70mmol3-[(aminomethyl phenyl in the 60ml hydrogen furans) the sulfonyloxy methyl]-1-pyrrolidine carboxylic acid tertiary butyl ester.With reaction mixture reflux 12 hours.Behind cooling and the dilute with water, evaporation removes and desolvates.Resistates with dichloromethane extraction and with organic phase wash with water, dry and concentrate, obtain expecting product.
Step b:1-(3-pyrrolidyl methyl)-1H-indole-6-carbonitrile hydrochloride
The 40ml trifluoroacetic acid is added in the solution of the described compound of 70mmol previous step in the 290ml methylene dichloride.Reaction mixture was at room temperature stirred 2 hours 30 minutes.After removing solvent by evaporation, resistates is dissolved in the methylene dichloride and with the washing of 1M sodium carbonate solution.With the organic phase drying, concentrate and by chromatogram chromatography purification on silica gel, as eluent, obtain expecting product with methylene chloride/ammonia mixture (85/15/1).By obtaining corresponding hydrochloride with the effect of volumetric soiutions of HCl in ethanol.
Elemental microanalysis:
C H N Cl
% calculated value 64.24 6.16 16.05 13.54
% measured value 64.35 6.40 15.96 13.67
Embodiment 5:1-[(1-benzyl-3-pyrrolidyl) methyl]-1H-indole-6-carbonitrile hydrochloride
4.4mmol salt of wormwood and 4.4 bromotoluenes are added in the solution of 4.4mmol embodiment 4 described compounds in the 20ml acetonitrile.Reflux and stir after 2 hours 30 minutes, dilute with the reaction mixture cooling and with methylene dichloride/water mixture.With organic phase separation, dry and concentrated.Resulting resistates by chromatogram chromatography purification on silica gel, as eluent, is obtained expecting product with ethyl acetate/hexanaphthene mixture (50/50).By obtaining corresponding hydrochloride with the effect of volumetric soiutions of HCl in ethanol.
Elemental microanalysis:
C H N Cl
% calculated value 71.68 6.30 11.64 10.08
% measured value 71.40 6.38 11.65 10.05
Embodiment 6:1-{[1-(3-benzyl chloride base)-3-pyrrolidyl] methyl }-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, obtain expecting product for bromotoluene with 3-benzyl chloride base bromo.Elemental microanalysis:
C H N Cl
% calculated value 65.29 5.48 10.88 9.18
% measured value 65.16 5.54 10.72 9.04
Embodiment 7:1-[(1-styroyl-3-pyrrolidyl) methyl]-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, replace bromotoluene to obtain expecting product with phenethyl bromide.Elemental microanalysis:
C H N Cl
% calculated value 72.22 6.61 11.48 9.69
% measured value 71.88 6.68 11.45 9.74
Embodiment 8:1-{[1-(2-benzyl chloride base)-3-pyrrolidyl] methyl }-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, obtain expecting product for bromotoluene with 2-benzyl chloride base bromo.Elemental microanalysis:
C H N Cl
% calculated value 65.29 5.48 10.88 9.18
% measured value 65.42 5.58 10.78 9.03
Embodiment 9:1-(3-pyrrolidyl methyl)-1H-indoles-5-nitrile hydrochloride
According to embodiment 4 described methods, replace the 6-cyanoindole to obtain expecting product with the 5-cyanoindole.
Elemental microanalysis:
C H N Cl
% calculated value 62.24 6.16 16.05 13.54
% measured value 64.10 6.10 15.86 13.68
Embodiment 10:1-[(1-benzyl-3-pyrrolidyl) methyl]-1H-indoles-5-nitrile hydrochloride
According to embodiment 5 described methods, replace embodiment 4 described compounds to obtain expecting product with the described compounds of embodiment 9.
Elemental microanalysis:
C H N Cl
% calculated value 71.68 6.30 11.94 10.08
% measured value 71.47 6.29 11.81 10.20
Embodiment 11:1-{[1-(3-benzyl chloride base)-3-pyrrolidyl] methyl }-1H-indoles-5-nitrile hydrochloride
According to embodiment 5 described methods, replace embodiment 4 described compounds and replace bromotoluene to obtain expecting product with 3-benzyl chloride base bromo with the described compounds of embodiment 9.
Elemental microanalysis:
C H N Cl
% calculated value 65.29 5.48 10.88 9.18
% measured value 65.45 5.47 10.61 9.29
Embodiment 12:1-[(1-styroyl-3-pyrrolidyl) methyl]-1H-indoles-5-nitrile hydrochloride
According to embodiment 5 described methods, replace embodiment 4 described compounds and replace bromotoluene to obtain expecting product with phenethyl bromide with the described compounds of embodiment 9.
Elemental microanalysis:
C H N Cl
% calculated value 72.22 6.61 11.48 9.69
% measured value 72.22 6.75 11.20 9.61
Embodiment 13:1-{[1-(2-benzyl chloride base)-3-pyrrolidyl] methyl }-1H-indoles-5-nitrile hydrochloride
According to embodiment 5 described methods, replace embodiment 4 described compounds and replace bromotoluene to obtain expecting product with 2-benzyl chloride base bromo with the described compounds of embodiment 9.
Elemental microanalysis:
C H N Cl
% calculated value 65.29 5.48 10.88 9.18
% measured value 65.78 5.57 10.64 9.16
Embodiment 14:1-(3-{4-[4-(trifluoromethyl)-2-pyridyl]-the 1-piperazinyl } propyl group)-1H-indole-6-carbonitrile dihydrochloride
According to embodiment 1 described method, in step c, replace 5-methoxyl group-4-(1-piperazinyl) pyrimidine to obtain expecting product with 4-trifluoromethyl-2-(1-piperazinyl)-pyridine.
Elemental microanalysis:
C H N Cl
% calculated value 54.33 4.97 14.40 14.45
% measured value 54.33 5.04 14.10 14.20
Embodiment 15:1-{3-[4-(5-methoxyl group-4-pyrimidyl)-1,4-diaza -1-yl] propyl group)-1H-indole-6-carbonitrile dihydrochloride
According to embodiment 1 described method, in step c, replace 5-methoxyl group-4-(1-piperazinyl) pyrimidine to obtain expecting product with 4-(1,4-diaza -1-yl)-5-methoxyl group-pyrimidine.
Elemental microanalysis:
C H N Cl
% calculated value 57.02 6.09 18.14 15.30
% measured value 57.39 6.23 17.86 15.07
Embodiment 16:1-{3-[4-(2-p-methoxy-phenyl)-1-piperazinyl] propyl group)-1H-indole-6-carbonitrile dihydrochloride
According to embodiment 1 described method, in step c, replace 5-methoxyl group-4-(1-piperazinyl) pyrimidine to obtain expecting product with 1-(2-p-methoxy-phenyl) piperazine.
Elemental microanalysis:
C H N Cl
% calculated value 61.75 6.31 12.52 15.85
% measured value 61.50 6.24 12.20 15.54
Embodiment 17:1-{[1-(3-phenyl propyl)-3-pyrrolidyl] methyl }-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, replace bromotoluene to obtain expecting product with 1-(3-bromopropyl) benzene.
Elemental microanalysis:
C H N Cl
% calculated value 72.71 6.90 11.06 9.33
% measured value 72.67 6.99 10.92 9.56
Embodiment 18:1-{[1-(3-phenyl propyl)-3-pyrrolidyl] methyl }-1H-indoles-5-nitrile hydrochloride
According to embodiment 5 described methods, replace embodiment 4 described compounds and obtain expecting product with 1-(3-bromopropyl) benzene replacement bromotoluene with the described compounds of embodiment 9.
Elemental microanalysis:
C H N Cl
% calculated value 72.71 6.90 10.06 9.33
% measured value 72.48 6.91 10.84 9.21
Embodiment 19:1-(1-[2-(1-naphthyl) ethyl]-the 3-pyrrolidyl } methyl)-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, replace bromotoluene to obtain expecting product with 1-(2-bromotrifluoromethane) naphthalene.
Elemental microanalysis:
C H N Cl
% calculated value 75.08 6.30 10.10 8.52
% measured value 74.67 6.36 9.82 8.57
Embodiment 20:1-{[1-(3-chlorobenzene ethyl)-3-pyrrolidyl] methyl }-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, replace bromotoluene to obtain expecting product with 1-(2-bromotrifluoromethane)-3-chlorobenzene.
Elemental microanalysis:
C H N Cl
% calculated value 66.00 5.79 10.50 17.71
% measured value 66.25 5.98 10.20 17.53
Embodiment 21:1-{[1-(4-anisole ethyl)-3-pyrrolidyl] methyl }-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, replace bromotoluene to obtain expecting product with 1-(2-bromotrifluoromethane)-4-anisole.
Elemental microanalysis:
C H N Cl
% calculated value 69.77 6.62 10.61 8.95
% measured value 69.64 6.44 10.36 8.98
Embodiment 22:1-{[1-(3-fluorobenzene ethyl)-3-pyrrolidyl] methyl }-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, replace bromotoluene to obtain expecting product with 1-(2-bromotrifluoromethane)-3-fluorobenzene.
Elemental microanalysis:
C H N Cl
% calculated value 68.83 6.04 10.95 9.24
% measured value 68.24 5.98 10.55 9.46
Embodiment 23:1-(1-[2-(2-naphthyl) ethyl]-the 3-pyrrolidyl } methyl)-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, replace bromotoluene to obtain expecting product with 2-(2-bromotrifluoromethane) naphthalene.
Elemental microanalysis:
C H N Cl
% calculated value 75.08 6.30 10.10 8.52
% measured value 74.75 6.43 9.81 9.03
Embodiment 24:1-{[1-(2-chlorobenzene ethyl)-3-pyrrolidyl] methyl }-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, replace bromotoluene to obtain expecting product with 1-(2-bromotrifluoromethane)-2-chlorobenzene.
Elemental microanalysis:
C H N Cl
% calculated value 66.00 5.79 10.50 17.71
% measured value 66.98 5.95 10.43 17.58
Embodiment 25:1-{[1-(4-fluorobenzene ethyl)-3-pyrrolidyl] methyl }-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, replace bromotoluene to obtain expecting product with 1-(2-bromotrifluoromethane)-4-fluorobenzene.
Elemental microanalysis:
C H N Cl
% calculated value 68.83 6.04 10.95 9.24
% measured value 68.93 6.10 10.48 8.96
Embodiment 26:1-(1-[2-(6-chloro-2-oxo-2,3-dihydro-1H-indoles-5-yl) ethyl]-the 3-pyrrolidyl } methyl)-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, with 6-chloro-5--(2-chloroethyl)-1,3-dihydro-indoles-2 ketone replaces bromotoluene to obtain expecting product.
Elemental microanalysis:
C H N Cl
% calculated value 63.30 5.31 12.30 15.57
% measured value 63.68 5.54 11.58 14.88
Embodiment 27:1-(1-[2-(7-methyl-5-oxo-5H-[1,3] thiazole also [3,2-a] pyrimidine-6-yl) ethyl]-the 3-pyrrolidyl } methyl)-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, with 6-(2-chloroethyl)-7-methyl-[1,3] thiazole also [3,2-a] pyrimidine-5-ketone replace bromotoluene to obtain expecting product.
Elemental microanalysis:
C H N Cl
% calculated value 60.85 5.33 15.43 7.06
% measured value 59.23 5.63 14.16 6.56
Embodiment 28:1-(1-[2-(2,4-dioxo-1,4-dihydro-3-(2H)-quinazolyl) ethyl]-the 3-pyrrolidyl } methyl)-1H-indole-6-carbonitrile hydrochloride
According to embodiment 5 described methods, with 3-(2-chloroethyl)-(1H)-quinazoline-2,4-ketone replaces bromotoluene to obtain expecting product.
Elemental microanalysis:
C H N Cl
% calculated value 64.07 5.38 15.57 7.88
% measured value 63.56 5.56 14.58 7.82
Embodiment 29:1-{3-[cyclohexyl (methyl) amino] propyl group }-the 1H-indole-6-carbonitrile
According to embodiment 1, the described method of step c replaces 5-methoxyl group-4-(1-piperazinyl) pyrimidine to obtain expecting product with N-methyl-cyclohexyl amine.
Embodiment 30:1-[3-(benzylamino) propyl group]-the 1H-indole-6-carbonitrile
According to embodiment 1, the described method of step c replaces 5-methoxyl group-4-(1-piperazinyl) pyrimidine to obtain expecting product with the N-benzylamine.
Embodiment 31:1-{3-[phenyl (methyl) amino] propyl group }-the 1H-indole-6-carbonitrile
According to embodiment 1, the described method of step c replaces 5-methoxyl group-4-(1-piperazinyl) pyrimidine to obtain expecting product with methylphenylamine.
Embodiment 32:1-(3-{[2-(piperidino) ethyl] amino } propyl group)-the 1H-indole-6-carbonitrile
According to embodiment 1, the described method of step c replaces 5-methoxyl group-4-(1-piperazinyl) pyrimidine to obtain expecting product with N-(2-amino-ethyl) piperidines.
Embodiment 33:1-(3-{[2-(1-pyrrolidyl) ethyl] amino } propyl group)-the 1H-indole-6-carbonitrile
According to embodiment 1, the described method of step c replaces 5-methoxyl group-4-(1-piperazinyl) pyrimidine to obtain expecting product with N-(2-amino-ethyl) tetramethyleneimine.
Embodiment 34:1-[3-(4-morpholinyl) propyl group]-the 1H-indole-6-carbonitrile
According to embodiment 1, the described method of step c obtains expecting product with morpholino for 5-methoxyl group-4-(1-piperazinyl) pyrimidine.
Embodiment 35:1-{2-[4-(5-methoxyl group-4-pyrimidyl)-1-piperazinyl] ethyl }-1H-indole-6-carbonitrile dihydrochloride
According to embodiment 1 described method, in step a, replace 3-bromo-1-propyl alcohol to obtain expecting product with 2-bromo-1-ethanol.
Embodiment 36:1-{2-[4-(2-p-methoxy-phenyl-1-piperazinyl] ethyl)-1H-indole-6-carbonitrile dihydrochloride
According to embodiment 1 described method, in step a, replace 3-bromo-1-propyl alcohol, and in step c, obtain expecting product with 1-(2-p-methoxy-phenyl) piperazine replacement 5-methoxyl group-4-(1-piperazinyl) pyrimidine with 2-bromo-1-ethanol.
Pharmaceutical research
Embodiment A: in rat, measure affinity with the serotonin reuptake transporter site
By with [
3H]-competitive assay of Paroxetine measures the affinity of The compounds of this invention.Prepare film and divide three parts to use 0.25nM[by rat volume cortex
3H]-Paroxetine and cold part with the final volume of 0.4ml in 25 ℃ of following incubations 2 hours.Incubation buffering liquid contains 50mM TRIS-HCl (pH7.4), 120mM NaCl and 5mM KCl.Use 10 μ M citaloprams to measure non-specific binding.When incubation finishes, wash three times with the strainer filtering mixt and with 5ml refrigerative damping fluid.Measure the radioactivity that is retained on the strainer by liquid scintillation counting(LSC).By nonlinear regression analysis in conjunction with thermoisopleth to determine IC
50Value.The latter uses the Cheng-Prusoff equation to be converted into dissociation constant (K
i):
K
i＝IC
50/{(L/K
d)-1}
Wherein L be [
3H]-concentration and the K of Paroxetine
dBe dissociation constant (0.13nM).
The compounds of this invention has very high affinity to the serotonin reuptake transporter site.
For instance, the dissociation constant K of the compound of embodiment 1
iBe 9.8 * 10
-9M.
Embodiment B: measure and 5-HT
2CThe affinity of acceptor
By with [
3H]-competitive assay of mesulergine (mesulergine) measures the affinity of The compounds of this invention, and incubation buffering liquid is Hepes 20mM, EDTA 2mM, xitix 0.1% (pH=7.7), and heated culture temperature is 22 ℃.[
3H]-the dissociation constant K of mesulergine
DBe 0.54mM.Use 1 μ M mianserin to determine non-specific binding, also be each experiment with reference to product.
When incubation finishes, wash three times through filter GF/B-Unifilter (handling) filtering mixt and with incubation buffering liquid with PEI (0.1%).
Measure the radioactivity that is retained on the strainer by liquid scintillation counting(LSC).By nonlinear regression analysis in conjunction with thermoisopleth to determine IC
50Value.The latter is converted into dissociation constant K
i
The compounds of this invention is to 5-HT
2CAcceptor has very high affinity, and its dissociation constant is 10
-8-10
-9M.
Embodiment C: pharmaceutical composition
The prescription of 1000 tablets of preparation, the dosage that each tablet comprises is 10mg:
The compound 10g of embodiment 1
Hydroxypropylcellulose 2g
Wheat starch 10g
Lactose 100g
Magnesium Stearate 3g
Talcum 3g
Claims (8)
1, formula (I) compound, its enantiomorph, diastereomer and with the additive salt of pharmaceutically acceptable acid or alkali:
Wherein:
R
1And R
2The expression hydrogen atom,
A represents straight or branched C
1-C
6Alkylidene group,
G
1The expression Heterocyclylalkyl, with A by any one articulating point bonding and optionally on any one site of ring replaced by following groups: the aryl of optional replacement, wherein moieties is the aryl-C of the optional replacement of straight or branched
1-C
6Alkyl, the optional heteroaryl that replaces or wherein moieties be the heteroaryl-C of the optional replacement of straight or branched
1-C
6Alkyl,
Wherein,
" Heterocyclylalkyl " is meant saturated 4-8 unit cyclic group, contains 1 or 2 nitrogen and/or Sauerstoffatom, is selected from piperazinyl, 1,4-diaza base and pyrrolidyl,
" aryl " is meant phenyl and naphthyl,
" heteroaryl " is meant monocycle or two rings, unsaturated or part is undersaturated, " the optional replacement " the described group of expression that is selected from the group of pyridyl, pyrimidyl, indolinyl, thiazole and pyrimidyl and dihydroquinazoline base and is used for term " aryl ", " arylalkyl ", " heteroaryl " and " heteroarylalkyl " is replaced by a following groups on its circular part: halogen atom and/or straight or branched C
1-C
6Alkyl, straight or branched C
1-C
6Alkoxyl group, moieties are the perhalogeno C of straight or branched
1-C
6Alkyl group, and heteroaryl and heteroarylalkyl also can be replaced by oxo group.
2, according to formula (I) compound of claim 1, its enantiomorph, diastereomer and with the additive salt of pharmaceutically acceptable acid or alkali, wherein connect cyano group in the 6-position of indyl.
3, according to formula (I) compound of claim 1, its enantiomorph, diastereomer and with the additive salt of pharmaceutically acceptable acid or alkali, wherein connect cyano group in the 5-position of indyl.
4, according to formula (I) compound of claim 1 and with the additive salt of pharmaceutically acceptable acid, be 1-{3-[4-(5-methoxyl group-4-pyrimidyl)-1-piperazinyl] propyl group-1H-indole-6-carbonitrile dihydrochloride.
5, according to formula (I) compound of claim 1 and with the additive salt of pharmaceutically acceptable acid, be 1-{[1-(2-chlorobenzene ethyl)-3-pyrrolidyl] methyl-the 1H-indole-6-carbonitrile.
6, a kind of preparation is characterized in that formula (II) compound is used as raw material according to the method for formula (I) compound of claim 1:
R wherein
1And R
2Each defines suc as formula (I),
After formula (II) compound is handled in alkaline medium, it can be stood
The effect of → formula (III) compound:
P-A-G
1 (III)
Wherein A and G
1Define suc as formula (I), and P represents leavings group, obtains formula (I) compound,
Perhaps
The effect of → formula (IV) compound:
Hal-A-OH (IV)
Wherein A defines suc as formula (I), and Hal represents halogen atom, obtains the formula V compound:
R wherein
1, R
2Define suc as formula (I) with A, after being converted into leavings group, the formula V compound stood the effect of formula (VI) compound in alkaline medium with hydroxyl functional group bromination or with the latter:
G
1-H (VI)
G wherein
1Define suc as formula (I), obtain formula (I) compound, work as group G
1When representing unsubstituted Heterocyclylalkyl, can use conventional organic chemical reactions that it is in the end replaced in the step so that the defined substituting group of drawing-in system (I),
Formula (I) compound:
-randomly, can be according to conventional purification technique purifying,
-randomly, can be separated into its isomer according to conventional isolation technique,
-randomly, be converted into its additive salt with pharmaceutically acceptable acid or alkali.
7, pharmaceutical composition, comprise separately at least a according among the claim 1-5 each formula (I) compound as activeconstituents or with one or more inertia, nontoxic pharmaceutically acceptable vehicle or carrier combinations.
8, according to the pharmaceutical composition of claim 7, comprise at least aly, be used for preparing the medicine that is used as serotonin reuptake inhibitor in the treatment of dysthymia disorders, obsessive-compulsive disorder, phobia, impulsion disease, bulimia nervosa and the anxiety disorder relevant with drug abuse according to each activeconstituents among the claim 1-5.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9900801 | 1999-01-26 | ||
| FR9900801A FR2788772B1 (en) | 1999-01-26 | 1999-01-26 | NOVEL CYANO-INDOLE INHIBITOR COMPOUNDS FOR SEROTONIN RECAPTURE, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1266057A CN1266057A (en) | 2000-09-13 |
| CN1155570C true CN1155570C (en) | 2004-06-30 |
Family
ID=9541208
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB001011561A Expired - Fee Related CN1155570C (en) | 1999-01-26 | 2000-01-26 | Novel cyano-indole serotonin reextracted inhibitor compound, its preparation process and medicinal compositions having same |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US6239129B1 (en) |
| EP (1) | EP1023898B1 (en) |
| JP (1) | JP2000212162A (en) |
| KR (1) | KR100445389B1 (en) |
| CN (1) | CN1155570C (en) |
| AT (1) | ATE234093T1 (en) |
| AU (1) | AU761084B2 (en) |
| BR (1) | BR0000158A (en) |
| CA (1) | CA2297279C (en) |
| DE (1) | DE60001591T2 (en) |
| DK (1) | DK1023898T3 (en) |
| EA (1) | EA003146B1 (en) |
| ES (1) | ES2193923T3 (en) |
| FR (1) | FR2788772B1 (en) |
| HK (1) | HK1029584A1 (en) |
| HU (1) | HUP0000308A2 (en) |
| MX (1) | MXPA00000856A (en) |
| NO (1) | NO314801B1 (en) |
| NZ (1) | NZ502494A (en) |
| PL (1) | PL338027A1 (en) |
| SI (1) | SI1023898T1 (en) |
| ZA (1) | ZA200000336B (en) |
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|---|---|---|---|---|
| JP2001247562A (en) * | 2000-03-07 | 2001-09-11 | Daicel Chem Ind Ltd | Amide compound and method of producing the compound |
| SE0004245D0 (en) | 2000-11-20 | 2000-11-20 | Pharmacia Ab | Novel compounds and their use |
| DE60142355D1 (en) * | 2000-11-20 | 2010-07-22 | Biovitrum Ab Publ | PIPERAZINYLPYRAZIN COMPOUNDS AS AGONISTS OR ANTAGONISTS ON THE SEROTONIN 5HT-2 RECEPTOR |
| PL364580A1 (en) | 2001-03-29 | 2004-12-13 | Bristol-Myers Squibb Company | Cyclopropylindole derivatives as selective serotonin reuptake inhibitors |
| DE60313895T2 (en) * | 2002-09-17 | 2008-01-17 | F. Hoffmann-La Roche Ag | 2,7-DISUBSTITUTED USES AND THEIR USE AS 5-HT6 MODULATORS |
| US7129264B2 (en) * | 2003-04-16 | 2006-10-31 | Bristol-Myers Squibb Company | Biarylmethyl indolines and indoles as antithromboembolic agents |
| WO2005056522A2 (en) * | 2003-12-04 | 2005-06-23 | National Health Research Institutes | Indole compounds |
| FR2884251B1 (en) * | 2005-04-08 | 2007-07-13 | Servier Lab | PIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
| WO2015066344A1 (en) | 2013-11-01 | 2015-05-07 | Arena Pharmaceuticals, Inc. | 5-ht2c receptor agonists and compositions and methods of use |
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| DK181190D0 (en) * | 1990-07-30 | 1990-07-30 | Lundbeck & Co As H | 3-ARYL-INDOL OR 3-ARYL-INDAZOL DERIVATIVES |
| TW270114B (en) * | 1993-10-22 | 1996-02-11 | Hoffmann La Roche | |
| DE19500689A1 (en) * | 1995-01-12 | 1996-07-18 | Merck Patent Gmbh | Indole piperidine derivatives |
| US5912256A (en) * | 1996-06-20 | 1999-06-15 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
| AU5343298A (en) * | 1997-01-13 | 1998-08-03 | Yamanouchi Pharmaceutical Co., Ltd. | 5-ht2c receptor agonists and aminoalkylindazole derivatives |
-
1999
- 1999-01-26 FR FR9900801A patent/FR2788772B1/en not_active Expired - Fee Related
-
2000
- 2000-01-24 CA CA002297279A patent/CA2297279C/en not_active Expired - Fee Related
- 2000-01-24 JP JP14544A patent/JP2000212162A/en active Pending
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- 2000-01-26 DK DK00400193T patent/DK1023898T3/en active
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| Publication number | Publication date |
|---|---|
| MXPA00000856A (en) | 2002-03-08 |
| EP1023898B1 (en) | 2003-03-12 |
| NO20000373L (en) | 2000-07-27 |
| NO20000373D0 (en) | 2000-01-25 |
| FR2788772A1 (en) | 2000-07-28 |
| CN1266057A (en) | 2000-09-13 |
| SI1023898T1 (en) | 2003-06-30 |
| PL338027A1 (en) | 2000-07-31 |
| US6239129B1 (en) | 2001-05-29 |
| EA200000068A3 (en) | 2000-10-30 |
| ATE234093T1 (en) | 2003-03-15 |
| EP1023898A1 (en) | 2000-08-02 |
| CA2297279C (en) | 2004-05-18 |
| FR2788772B1 (en) | 2001-03-02 |
| ES2193923T3 (en) | 2003-11-16 |
| DE60001591T2 (en) | 2003-12-24 |
| AU761084B2 (en) | 2003-05-29 |
| NZ502494A (en) | 2001-06-29 |
| EA003146B1 (en) | 2003-02-27 |
| JP2000212162A (en) | 2000-08-02 |
| DE60001591D1 (en) | 2003-04-17 |
| EA200000068A2 (en) | 2000-08-28 |
| DK1023898T3 (en) | 2003-06-10 |
| ZA200000336B (en) | 2000-08-15 |
| HUP0000308A2 (en) | 2002-06-29 |
| KR20010006587A (en) | 2001-01-26 |
| AU1355300A (en) | 2000-07-27 |
| HK1029584A1 (en) | 2001-04-06 |
| CA2297279A1 (en) | 2000-07-26 |
| KR100445389B1 (en) | 2004-08-25 |
| HU0000308D0 (en) | 2000-03-28 |
| BR0000158A (en) | 2000-09-19 |
| NO314801B1 (en) | 2003-05-26 |
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